tbuckley/cabot-search huggingface dataset:
P01.02.A WHOLE-BRAIN STRUCTURAL CONNECTIVITY PREDICTS COGNITIVE OUTCOMES IN PRETREATED PATIENTS WITH WHO GRADE 3 OR 4 GLIOMAS
Authors: M Friedrich, G Stoffels, C P Filss, P Lohmann, F M Mottaghy, C Weiss Lucas, M I Ruge, N J Shah, S Caspers, K J Langen, G R Fink, N Galldiks, M Kocher
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioma patients frequently suffer from cognitive dysfunction potentially related to brain damage caused by tumor invasion or therapeutic intervention. We hypothesized that, as in other neurological disorders, the long-term outcome of cognitive functions in glioma patients critically depends on maintaining the structural connectivity of multiple interconnected networks. PATIENTS AND METHODS One hundred and twenty-one glioma patients (median age, 52 years; median ECOG score, 1) with histomolecularly characterized CNS WHO grade 3 or 4 gliomas were investigated after a median time of 14 months (range, 1-214 months) following first-line therapy, including resection and chemoradiation with alkylating agents. Hybrid amino acid PET/MR imaging using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine, a brain-networks-based cortical parcellation into nodes, and advanced fiber tractography tools were used for constructing fiber-count-weighted connectivity matrices. Cognitive performance was measured by ten different tests concerning various cognitive domains. The connectivity matrices and the patients' test scores were applied to a machine learning-based model that identified critical fiber connections, cortical nodes, and involved networks for predicting cognitive performance in the assessed domains. RESULTS Compared to a matched cohort of healthy subjects, the cognitive scores of the patients were significantly lower in 9 of 10 cognitive tests. The most affected domains were executive function/concept-shifting (-72%), attention/processing speed (relative performance, -53%), followed by semantic word fluency (-25%), verbal working and semantic memory (-8 and -22%, respectively), and visual working memory (-11 to -20%). For each cognitive test, a subset of connections (median number, 254; range, 32-542) was identified whose fiber count sum showed a correlation with the actual scores in a linear model (median R2, 0.37; range, 0.16-0.44). Leave-one-out cross-validation confirmed the model's generalizability in 7 of 10 tests (median correlation coefficient for predicted compared to observed scores, 0.47; range 0.39-0.57). The distribution of critical cortical regions (node degree of ≥ 5 predictive edges), found in 90% of the cross-validation iterations, varied considerably between domains. These included predominantly left-sided cortical nodes of the visual, somatomotor, dorsal/ventral attention, and default mode networks. Highly critical nodes (degree of 15-20 predictive edges) included the default-mode network’s left temporal and bilateral posterior cingulate cortex. CONCLUSION These results suggest that the cognitive performance of pretreated glioma patients is strongly related to the structural connectivity within multiple brain networks and depends on the integrity of known network hubs.
KS03.7.A INDEPENDENT PROGNOSTIC ROLE OF METHYLATION CLASS IN ATYPICAL AND MALIGNANT MENINGIOMA UNDERGOING ADJUVANT HIGH-DOSE RADIOTHERAPY: COMPREHENSIVE MOLECULAR ANALYSIS OF EORTC TRIAL 22042-26042
Authors: S L N Maas, P Sievers, D Weber, M Weller, M J van den Bent, M J Mair, J M Kros, F Caparrotti, V Salvador, S M Peerdeman, J Casas, T Gorlia, F Sahm, M Preusser
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In EORTC trial 22042-2604 WHO grade 2 and 3 meningioma patients underwent adjuvant high dose radiotherapy. The current study investigated clinicopathological correlations and the prognostic impact of genetic and epigenetic molecular factors in EORTC 22042-26042 trial patients. METHODS For patients that gave consent for additional molecular analysis of the resected tumor specimens (53 of 78 enrolled patients), Illumina Infinium Methylation EPIC BeadChip DNA methylation arrays and next generation sequencing (NGS) panels were performed to investigate the meningioma methylation class, and the presence of mutations in AKT1, TRAF7, BAP1, NF2 and the TERT-promotor as well as loss of chromosomes 1p and 22q and/or homozygous loss of CDKN2A/B. The cohort included 50 atypical and 3 malignant meningiomas per local assessment according to WHO classification at the time of patient enrollment. Factors significant at 10% significance in the univariate and interaction factor analyses were included in multivariate analyses with stepwise selection at the same significance. RESULTS The Cox multivariate analyses identified meningioma methylation class as a significant independent prognostic factor for progression-free survival (PFS) and overall survival (OS) measured from patient registration in the trial, respectively Chromosome 1p loss was significantly associated with PFS but not with OS. Age was significantly associated with OS but not with PFS. Due to small number of cases and/or events the prognostic value of homozygous deletion of CDKN2A/B (n=2) and TERT-promotor mutation (n=2) could not be adequately studied. CONCLUSIONS In this cohort of WHO grade 2 and 3 meningioma undergoing high-dose adjuvant radiotherapy, meningioma methylation class was identified as an independent prognostic factor for PFS and OS. Chromosome 1p loss was associated with reduced PFS but not OS. Larger cohorts are required to validate our findings.
P15.03.B MOLECULARLY TARGETED PROTEASE-ACTIVATED PROBES FOR THE VISUALIZATION OF GLIOBLASTOMA: A COMPARISON WITH 5-ALA
Authors: D Konecna, P Vymola, N Ternerova, B Vymolova, E Garcia-Borja, R Mateu, F Sroubek, J Pankrac, J Widen, M Bogyo, D Netuka, A Sedo, P Busek
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Surgery is the main treatment option for glioblastoma. However, due to its highly infiltrative growth, it is difficult to distinguish the tumor from normal brain tissue. The aim of this work was to evaluate the ability of recently developed molecularly targeted near-infrared (NIR) protease-activated probes to be specifically activated in brain tumor tissue and to compare the most promising candidate with the FDA approved 5-aminolevulinic acid (5-ALA). MATERIAL AND METHODS The cysteine cathepsin-cleavable probes 6QC-ICG and 6QC-Cy5 (single-substrate), the cysteine cathepsin and caspase 3-cleavable dual, AND-GATE substrate probes AG2-FNIR and AG2-Cy5 (double-substrate) were administered intravenously to mice with orthotopic tumors. Activation of the probes was further evaluated in glioma cell lines, patient-derived glioma stem-like cells, M2-polarized macrophages in vitro, and biopsy material from patients with glioblastoma ex vivo. Tumor to normal brain tissue fluorescence ratio (TNR) was quantified in tissue sections using preclinical and clinical visualization platforms. Fluorescence in tissue homogenates and cell suspensions was quantified by spectrofluorimetry. RESULTS 6QC-ICG was activated in glioma cells and macrophages in vitro and the resulting fluorophore accumulated intracellularly. In experimental glioblastomas, single- and double-substrate probes visualized tumor tissue with a minimum signal generated in healthy brain. TNR was highest for 6QC-ICG and AG2-FNIR. Nevertheless, the signal intensity was higher for 6QC-ICG. Using xenograft and syngeneic mouse models, we confirmed the ability of 6QC-ICG to specifically visualize glioma tissue based on image analysis and spectrofluorimetric measurement. Furthermore, we confirmed that 6QC-ICG was activated in human glioblastoma tissue using ex vivo biopsy material and could be visualized on a clinical visualization platform. Finally, a comparison with 5-ALA in animals co-administered with both compounds revealed a higher TNR for 6QC-ICG in experimental glioblastomas. CONCLUSION 6QC-ICG is activated by glioma cells and tumor-associated macrophages leading to a high contrast between tumor and non-tumorous brain tissue that is superior to that of the current standard 5-ALA. In addition to their well-defined mechanism of action, the protease-activated probes using NIR fluorophores such as ICG offer the advantage of low absorption and scattering of the NIR light and lower tissue autofluorescence. Our results thus suggest the potential of 6QC-ICG to become a targeted agent for the intraoperative detection of glioblastoma. Supported by National Institute for Cancer Research (LX22NPO5102), Centre for Tumour Ecology (CZ.02.1.01/0.0/0.0/16_019/0000785), EATRIS-CZ (LM2023053), Cooperatio Program-,,Oncology and Haematology", Ministry of Health of the Czech Republic (NV190300501).
P11.57.B OVER ONE YEAR OF SURVIVAL DIFFERENCE BETWEEN DISTINCT COHORTS OF GLIOBLASTOMA PATIENTS
Authors: M T C Poon, P Y M Woo, A El Helali, P M Brennan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Understanding the differences in outcomes based on study and patient characteristics can inform better research designs and improve the interpretation of translational glioblastoma studies. MATERIAL AND METHODS This study compared the clinical features and median overall survival (mOS) of 2,203 patients from two genomic cohorts (The Cancer Genome Atlas [TCGA] and the Chinese Glioma Genome Atlas [CGGA]) and two consecutive regional cohorts (Hong Kong [HK] and Southeast [SE] Scotland) with histologically confirmed glioblastoma. RESULTS A total of 2,203 patients with newly diagnosed glioblastoma were identified, including 414 from SE Scotland, 1,033 from HK, 510 from TCGA, and 246 from CGGA. In patients who have available treatment data and received standard chemoradiotherapy, the mOS was 35.2 months (95%CI 27.1-50.2) in SE Scotland, 22.2 (95%CI 19.0-25.5) in HK, and 14.1 months (95%CI 11.8-17.9) in TCGA. Using data from 1,023 patients from SE Scotland (N=414) and HK (N=609) where sufficient data was available, the multivariable Cox regression model did not demonstrate survival differences among patients treated in HK compared to those treated in SE Scotland (hazard ratio 0.93; 95%CI 0.80-1.08; p=0.30). CONCLUSION Survival differences between distinct cohorts of glioblastoma patients warrant further investigations into associated determinants to assess reproducibility and generalizability of research.
P13.03.B PREDICTING FUNCTIONAL CONNECTIVITY FROM STRUCTURAL CONNECTIVITY IN GLIOMA PATIENTS
Authors: L Smolders, W De Baene, L Florack, R van der Hofstad, G Rutten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The mechanism by which activity in the brain relates to its anatomical structure is a central topic of research in neuroscience. In recent years, this relation has been studied in the context of network science, where anatomical white-matter connections are captured in Structural Connectivity (SC) and statistical dependence between grey-matter activity in Functional Connectivity (FC). The relation between SC and FC is poorly understood at an individual level, especially in glioma patients. Developing methods to predict FC from SC in these patients could improve our understanding of how gliomas affect brain function, and consequently cognition. Furthermore, a model accurate at individual patient level could aid in clinical decision-making by identifying eloquent areas and connections in individuals. MATERIAL AND METHODS Building on earlier work predicting FC from SC in healthy subjects, we trained a deep learning model on tractography and resting-state fMRI data of 288 glioma patients to predict FC at an individual level. Since our sample size is modest in the context of deep learning, we attempted to improve accuracy by pre-training the model on a large set of healthy subjects. This way, the model should learn baseline patterns in SC and FC before learning the specific patterns associated with glioma patients. We used data from 1052 subjects of the Human Connectome Project and 633 subjects of the Cambridge Centre for Ageing and Neuroscience. Finally, we analyzed the effect of several factors on prediction accuracy: tumor volume, location and grade and patient age. RESULTS Training on only the patient set, the prediction model achieved an accuracy, measured as correlation between predicted and empirical FC, of 0.53 ± 0.03 at individual patient level. This is comparable with accuracy achieved in studies on healthy subjects. Pre-trained models did not improve accuracy. The model had more difficulty predicting FC in patients with a glioma in the insular region (p = 0.0014). No other factors were associated with accuracy. CONCLUSION Although further research is required to investigate the utility of FC predictions made by our model, our work is a first step towards predicting activity from brain structure in glioma patients at an individual level, since earlier research in patient populations has focused on group-level effects. We observed that predictions are less accurate in patients with a glioma in the insular region, which indicates that the relation between the structural and functional organization of the brain in this group is different from that in patients with tumors in other locations. Improving our methods to achieve higher accuracy could provide us, as a next step, with a tool to predict functional consequences of resective surgery on glioma patients, and consequently improve decision making by more accurately identifying eloquent regions at an individual level.
P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA
Authors: I Arrillaga-Romany, A Lassman, S L McGovern, S Mueller, L B Nabors, M van den Bent, M Vogelbaum, J E Allen, A S Melemed, R Tarapore, P Y Wen, T Cloughsey
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. MATERIAL AND METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.
P11.66.A COMBINATION OF TROFOSFAMIDE AND ETOPOSIDE IN RECURRENT GLIOBLASTOMA
Authors: T Schmidt, S Agkatsev, J Feldheim, C Oster, T Blau, U Sure, K Keyvani, C Kleinschnitz, M Stuschke, K Herrmann, C Deuschl, B Scheffler, S Kebir, M Glas, L Lazaridis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. MATERIAL AND METHODS We collected clinicopathological data from adult recurrent glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. RESULTS A total of n=22 recurrent glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 versus 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, p=0.0274) and median overall survival (9.0 versus 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, p=0.0003) were significantly prolonged compared to the control cohort (n=17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n=16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n=15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n=11/15, 73%). CONCLUSION This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients and may be associated with prolonged survival in recurrent glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
P20.15.A DESCRIPTIVE ANALYSIS OF A SERIES OF H3 K27-ALTERED DIFFUSE MIDLINE GLIOMAS IN CHILDREN AND ADULT POPULATION
Authors: C Salva de Torres, D Lopez Valbuena, M Gonzalez, M Vieito
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Molecular biomarkers have gained importance in providing diagnostic information for brain and spinal cord tumors. Diffuse midline gliomas (DMG) are now defined as H3 K27-altered. H3 K27M mutations were first described in pediatric diffuse pontine gliomas but can also be encountered in adult gliomas. The H3 K27M mutation often co-occurs with mutations in TP53, PDGFR, or ACVR1 and is mutually exclusive to IDH1/2 mutations and 1p/19q co-deletion. Surgical resection is often not feasible for its localization and the benefit of temozolomide (TMZ) is not clear as they are MGMT unmethylated; all of it conferring a poor prognosis. It has been suggested that pediatric patients (pts) have worse outcomes. Our aim was to describe pts with H3 K27-altered gliomas to better understand the characteristics of this population. MATERIAL AND METHODS We analyzed clinical, histological and molecular features of 6 adults and 10 pediatric pts diagnosed with H3 K27M-mutant gliomas between May 2016 and January 2021 in a tertiary hospital in Barcelona. RESULTS For adults, mean age at diagnosis was 34.6 years (range = 20 - 55 years). For children, mean age was 11.2 years (range = 4 - 17 years). Male-to-female ratio was 1:1. Tumors involved thalamus (adult = 3; pediatric = 3), pons (adult = 1; pediatric = 6), and pineal region (n = 1). Ki67 range was 2-60% (pediatric mean 32%, adult mean 20%). A molecular panel was analyzed in 8 pediatric pts and 1 adult. No EGFR amplifications were detected.Three of them had TP53 mutations and 2 had PDGFRA amplification. Only 2 pediatric pts had MGMT methylation. Regarding treatment, 9 pediatric and 4 adult pts underwent radiotherapy and TMZ as first-line, with a mean time to intervention of 5.6 months. One child went through palliative care. As a second-line treatment, re-irradiation was used in 3 pediatric pts and irinotecan-bevacizumab was used in 2 adults. One adult received up to 4 different treatments (TMZ chemoradiotherapy followed by adjuvant TMZ, irinotecan-bevacizumab, lomustine and metronomic TMZ).All 9 pediatric pts died, with a mean OS of 12.0 months. Among adults, 2 pts died, 10.5 and 31.2 months after diagnosis, 1 has progressed to first-line and is receiving PCV as second-line treatment, and 1 has completed Stupp regimen with stable disease as best response. CONCLUSION Although the sample size is limited, our cohort data resembles what has been previously reported in terms of clinical and molecular characteristics: diagnosed in young adults and pediatric pts, characterized by a midline location, a low rate of MGMT promoter methylation, frequent TP53 and PDGFR alterations, and poor prognosis. There is currently no consensus on optimal treatment sequence or best treatment for these pts. Collaborative effort and participation in clinical trials are needed to keep advancing in this poor prognosis disease.
JS04.5.A HEMIZYGOUS<i>CDKN2A</i> DELETION CONFERS WORSE SURVIVAL OUTCOMES IN IDH-MUTANT GLIOMAS
Authors: E Kocakavuk, K C Johnson, T S Sabedot, H C Reinhardt, H Noushmehr, R G W Verhaak
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The tumor suppressor gene CDKN2A is frequently deactivated in cancer. Homozygous CDKN2A deletion is a Grade 4 defining criterion for IDH-mutant gliomas. However, the prognostic value of hemizygous CDKN2A deletions is unclear. We assessed CNV profiles of 1238 initial and 479 recurrent IDHmut gliomas to evaluate the association of CDKN2A hemizygous deletions with overall survival (OS) outcomes. MATERIAL AND METHODS The GLASS primary/recurrent glioma dataset was used to infer CDKN2A status with DNAseq (n=210) and DNA methylation array (n=100) data. Validation was conducted using DFCI, MSKCC, TCGA and DKFZ cohorts. RESULTS Longitudinal analyses of IDH-mutant gliomas without 1p-/19q-codeletion showed significant increases in CDKN2A homozygous deletion from n=6 to n=23 (5% to 20%, P=0.0001, Fisher’s-exact test) and hemizygous deletion from n=19 to n=34 (17% to 30%, P=0.002) at recurrence. CDKN2A hemizygous deletions were significantly associated with poor OS at initial diagnosis (P&amp;lt;0.0001, log-rank test) and recurrence (P&amp;lt;0.0001), remaining significant in multivariable cox regression model that accounted for age, treatment with radiotherapy and/or alkylating agents, and 1p/19q-codeletion status: HR 2.40 (95%-CI: 1.31-4.37, P=0.004). Validation in independent datasets confirmed increased frequencies of CDKN2A hemizygous deletions in recurrent cases as well as the association between CDKN2A hemizygous deletion and worse OS in IDHmut gliomas. Using the DKFZ DNA methylation profiling dataset we further confirmed that CDKN2A status can be accurately assessed through DNAseq and DNA methylation array profiling. CONCLUSION CDKN2A hemizygous deletion is associated with significantly worse OS in initial and recurrent IDHmut gliomas. Similar to CDKN2A homozygous deletion, CDKN2A hemizygous deletion is enriched in post-treatment, recurrent IDHmut gliomas, confirming the value of CDKN2A status (re-)assessment in recurrences. Our results highlight the importance of incorporating CDKN2A status in diagnostic workup to inform prognosis and treatment strategies, revealing the previously unrecognized prognostic value of hemizygous CDKN2A deletions.